Abstract
In single cells, variably sized nanoscale chromatin structures are observed, but it is unknown whether these form a cohesive framework that regulates RNA transcription. Here, we demonstrate that the human genome is an emergent, self-assembling, reinforcement learning system. Conformationally defined heterogeneous, nanoscopic packing domains form by the interplay of transcription, nucleosome remodeling, and loop extrusion. We show that packing domains are not topologically associated domains. Instead, packing domains exist across a structure-function life cycle that couples heterochromatin and transcription in situ, explaining how heterochromatin enzyme inhibition can produce a paradoxical decrease in transcription by destabilizing domain cores. Applied to development and aging, we show the pairing of heterochromatin and transcription at myogenic genes that could be disrupted by nuclear swelling. In sum, packing domains represent a foundation to explore the interactions of chromatin and transcription at the single-cell level in human health.
| Original language | English (US) |
|---|---|
| Article number | eadq6652 |
| Journal | Science Advances |
| Volume | 11 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jan 10 2025 |
Funding
ChatGPT 4.0 was used to assist in calculating the radius of gyration of proteins. No AI tools or external reviewers were used for conceptualization, writing, synthesis, or direct analysis of results. Philanthropic support was received from R. and K. Goldman, the Christina Carinato Charitable Foundation, M. E. Holliday, I. Schneider, and D. Sachs. Computational analysis of Hi-C data was supported in part through the computational resources and staff contributions provided by the Genomics Compute Cluster, which is jointly supported by the Feinberg School of Medicine, the Center for Genetic Medicine, and Feinberg\u2019s Department of Biochemistry and Molecular Genetics, the Office of the Provost, the Office for Research, and Northwestern Information Technology. The Genomics Compute Cluster is part of Quest, Northwestern University\u2019s high-performance computing facility, with the purpose to advance research in genomics. We appreciate the support from the ENCODE Consortium in the generation and dissemination of publicly available datasets. We specifically want to thank the labs of B. Bernstein, T. Gingeras, P. Farnham, R. Myers, and J. Stamatoyannopoulo for the generation and publication of the data used within this manuscript. This work made use of the BioCryo facility (RRID:SCR_021288) of Northwestern University\u2019s NUANCE Center, which has received support from the SHyNE Resource (NSF ECCS-2025633), the IIN, and Northwestern\u2019s MRSEC program (NSF DMR-2308691). This work was supported by the National Science Foundation grant EFMA-1830961 (E.P.L., M.C., I.S., and V.B.), National Science Foundation grant EFMA-1830969 (E.P.L. and V.B.), National Science Foundation grant ECCS-2025633 (V.D.), National Science Foundation grant DMR-2308691 (V.D.), National Institutes of Health grant R01CA228272 (W.S.L., T.K., I.S., and V.B.), National Institutes of Health grant U54 CA268084 (W.S.L., L.M.C., L.M.A., E.P.L., T.K., K.L.M., M.C., I.S., and V.B.), National Institutes of Health grant U54 CA261694 (L.M.C., V.S., and V.B.), NIH Training Grant T32AI083216 (L.M.A.), NIH Training Grant T32GM132605 (T.K., L.M.C., and V.B.), Hyundai Hope on Wheels Hope Scholar Grant (K.L.M.), CURE Childhood Cancer Early Investigator Grant (K.L.M.), Alex\u2019s Lemonade Stand Foundation \u201CA\u201D award grant (K.L.M.), Ann and Robert H. Lurie Children\u2019s Hospital of Chicago under the Molecular and Translational Cancer Biology Neighborhood (K.L.M.), Northwestern University Starzl Scholar Award (L.M.A.), and National Institutes of Health National Center for Advancing Translational Sciences KL2TR001424 (K.L.M.).
ASJC Scopus subject areas
- General